Evidence Supporting a Paracrine Effect of IGF-1/VEGF on Human Mesenchymal Stromal Cell Commitment

Skeletal defect healing is strictly dependent on osteogenesis and efficient vascularization of engineered scaffolds. Insulin-like Growth Factor-1(IGF-1) and Vascular Endothelial Growth Factor (VEGF) are both involved in these processes. The in vitro administration of IGF-1 and VEGF association is able to modulate the osteoblastic or endothelial commitment of Mesenchymal Stromal Cells (MSCs) of different origin (e.g. periosteum and skin). In the present study, in order to deepen a possible paracrine effect of IGF-1 and VEGF on Periosteum Derived Progenitor Cells (PDPCs) and Skin-derived Mesenchymal Stromal Cells (S-MSCs) a transwell co-culture approach was used. We explored genes involved in endothelial and osteoblastic differentiation, those modulating mitogen-activated protein kinases (MAPK) and Phosphatidylinositol 3’-kinase (PI3K)-AKT signalling pathways as well as genes implicated in stemness (i.e. Sox2, Oct4 and Nanog). Periosteal cells, which are typically committed toward osteoblastogenesis, are driven in the direction of endothelial gene expression when influenced by S-MSCs. The latter, once influenced by PDPCs, lose their endothelial commitment and increase the expression of osteoblast associated genes. PI3K/AKT and MAPK signalling pathways seem to be markedly involved in this behaviour. Our results evidence that paracrine signals between MSCs may differently modulate their commitment in a bone microenvironment, opening stimulating viewpoints for skeletal tissue engineering strategies coupling angiogenesis and osteogenesis processes.